Anilino-pyridinium-maleimides



United States Patent O 3,335,147 ANILINO-PYRIDlNIUM-MALEIMIDES Marvin J. Karten, Yonkers, N.Y., assignor to US. Vitamin & Pharmaceutical Corporation, a corporation of Delaware No Drawing. Filed Apr. 29, 1965, Ser. No. 451,971 9 Claims. (Cl. 260-295) wherein R may be alkyl, substituted alkyl, cycloalkyl, aralkyl, heteroaryl, aryl; R and R may be hydrogen, lower alkyl, lower alkoxy, nitro, or halogen, and may be the same or different; and X is an anion of a mineral acid.

Preferably, R is an alkyl containing from 1 to 16 carbons, a lower alkoxy-lower alkyl, 21 carbethoxy-lower alkyl, a cycloalkyl containing from 5-6 carbon atoms, phenyl, naphthyl, phenyl-lower alkyl, thienyl, furyl, and furfuryl. Examples of preferred R groups are methyl, ethyl, butyl, isohexyl, dodecyl, myristyl, cyclohexyl, methoxyethyl, carbethoxymethyl, l-naphthyl, benzyl, and B-phenethyl.

X is preferably chloride, nitrate, sulfate or phosphate.

The compounds of this invention have potent topical anesthetic activity, and most of the compounds tested exhibited hypotensive activity when administered to mice.

The anilino-pyridinium-maleimides of this invention were conveniently prepared by mixing a molar amount of an appropriately N-substituted 2,3-dichloromaleimide with 2 molar amounts of an appropriately substituted pyridine in an inert solvent. To this mixture a molar amount of a l-[N-(Z-phenylethyl)-2-(4-nitroanilino)-3- maleimidylJpyridinium nitrate to proceed until no further precipitation occurred. Preferably, the reaction was brought to completion by refluxing the mixture at temperatures above 60 C. for a period of from about 1 to 2 hours. As a solvent I prefer a halogenated hydrocarbon such as chloroform, carbon tetrachloride, or dichloroethane. However, the reaction will proceed in other inert solvents such as, for example, benzene and acetonitrile. By following the procedure set forth above, compounds wherein X is chloride are obtained. By treating these compounds with an appropriate mineral acid such as, nitric, phosphoric or sulfuric acid, the corresponding nitrate, phosphate, or sulfate salt is obtained.

The intermediate N-substituted 2,3-dichloromaleimides were prepared according to the method described by Shapiro, Freedman and Karten in US. Patent 3,129,225.

The invention will appear more fully from the examples which follow, which are set forth by way of illustration only; and it is to be understood that it is intended here to cover all changes and modifications of the examples herein which do not constitute departures from the spirit and scope of the invention.

EXAMPLE I 1 [N Z-furfury i) -2-wmilinoI-3-maleim-idyl pyridinium chloride To a mixture of 10.0 g. (0.04 mole) of N-(2-furfuryl)- dichloromaleimide in 50 ml. of dichloroethane was added 6.3 g. (0.08 mole) of pyridine. The mixture turned purple and solution occurred. 3.3 g. (0.04 mole) of aniline then was added. The solution became less intense in color. The solution was refluxed for one hour on the steam bath during which time a large quantity of solid precipitated. The mixture was filtered while hot and washed with acetonitrile. The crude solid was recrystallized twice from methanol-ether and dried to give 9.5 g. of product, M.P. 249-251 (dec.).

EXAMPLE II N-[I-(Z-phenylethyl) -3-(4-nitroanilin0) -muleimidyl-4]- pyridimium nitrate The above procedure was used except that 4-nitroaniline was employed instead of aniline. The crude product, 12.4 g. Was dissolved in 150 ml. of hot water and filtered into 20 ml. of 5N HNO The yell-ow solid which precipitated was filtered, washed with water, ethanol and ether I and dried. It weighed 11.8 g. and gave a negative Beilstein test for halogen. It was recrystallized twice from hot water, washed with water, ethanol and ether and dried to give 7.0 g. of a yellow solid, M.P. 21021l.

In accordance with the procedures described in Examples I and II, the following compounds were prepared:

25 R1 Ra Ra X M.P., C.

CH3 H H Cl 284-286 iSO-CsHn- H H Cl 250-252 HC12H:5- H H C] 235-237 Ctl 1l H H Cl 227-232 3 EtOiCCHf- H H 01 201-203 C6H5CH2CH2- H H 01 235-236 CiHaO OHir- H H Cl 249-251 8H5 H H 01 248-25 C1oH7 H H 01 244-246 CaHsCHr- H H Cl 245-248 CBHECH2CH2- 4-CHa H Cl 225-230 CaHsCHaCHr- 4- -C6Hl1 H Cl 215-216 CaHsCHaCHz- H 4-CH3 Cl 239-241 CaHsCHqCHP H 4 OzN- N03 210-211 CeHsCHzCHr H 4-CHaO- N03 243-244 CsHsCHiCHz- H 2 OHaO- N03 101-106 CtHnCHaCHz- H H304 145-148 40 a Cyclohexyl. b 2-iuriuryl. l-naphthyl.

I claim: 1. A compound of the formula H O N wherein R is selected from the group consisting of an alkyl having from 1-16 carbons, a lower alkoxy-lower alkyl, a carbethoxy-lower alkyl, a cycloalkyl having from 5-6 carbons, phenyl, naphthyl, phenyl-lower alkyl, furyl, and furfuryl;

R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, nitro and halogen, and may be the same or different; and

X is an anion of a mineral acid.

2. The compound of claim 1 wherein R1 18 n-C H R and R are H, and

X is Cl.

3. Thee compound of claim 1 wherein R is cyclohexyl,

R and R are H, and

X is Cl.

4. The compound of claim 1 wherein R is Z-furfuryl,

R andR are H, and X is Cl. 5. The compound of claim 1 wherein 5 R1 is fl-phenethyl, R is 4(n-amy1), R is H, and X is Cl. 6. The compound of claim 1 wherein R is fi-phenethyl, R2 iS H, R, is Z-methoxy, and X is N0 7. A process for preparing a compound of the formula R: H u

B2 II N \J Cl wherein R is selected from the group consisting of an alkyl having from 1-16 carbon atoms, a lower alkoxylower alkyl, a carbethoxy-lower alkyl, a cycloalkyl having from 5-6 carbon atoms, phenyl, naphthyl, phenyl-lower alkyl, and furfuryl; and

R and R are .selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, nitro, and halogen, and may be the same or differentwhich comwith a two-molar amount of a compound of the structure in-an inert solvent, adding to said mixture a molar amount of a compound of the formula 2,592,273 4/1952 Goebel et a1. 260-567.6

WALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

A. L. ROTMAN, Assistant Examiner. 

1. A COMPOUND OF THE FORMULA 